Novel transcription factors modulating the development and function of pDCs and pDC-related cells

调节 pDC 和 pDC 相关细胞发育和功能的新型转录因子

基本信息

批准号：
10288643
负责人：
Juliana Idoyaga
金额：
$ 23.81万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288643
关键词：
Antiviral Agents Binding Biological Assay Cell Lineage Cell Maintenance Cell Proliferation Cell physiology Cells Charge Chromatin Collaborations Data Dendritic Cells Development Disease Fibrinogen Gene Expression Genetic Genetic Transcription Genomics Goals Human Human Cell Line ID2 gene Immune Immune response Individual Innate Immune Response Interferon Type I Interferons Knockout Mice Light Maintenance Modeling Mus Natural Killer Cells Outcome Play Regulation Research Role Site T-Cell Activation T-Lymphocyte TCF7L2 gene Testing Therapeutic Tissues Transcriptional Regulation Transposase Viral Virus Virus Diseases base cell type conditional knockout design genome-wide high dimensionality immunoregulation innate immune function mouse model new therapeutic target novel overexpression pathogen programs recruit response therapeutic development transcription factor

项目摘要

ABSTRACT Plasmacytoid dendritic cells (pDCs) and pDC-related cells are developmentally related innate immune cells capable of performing multiple functions essential for successful antiviral immune responses, including type I interferon secretion and T cell activation. The identity, i.e., development and function, of pDCs and pDC-related cells is controlled by the precise interaction of transcription factors (TFs). Tight regulation of transcriptional programs is essential to promote the appropriate response to pathogens while avoiding damage to healthy tissues. Thus, it is critical to unravel the transcriptional regulation of pDCs and pDC-related cells. Using a high- dimensional unbiased approach, we have recently discovered two conserved TFs that are specific and highly active in pDCs and pDC-related cells but not in other DC subsets. In two specific aims, we propose to explore the role of these TFs in determining the development and function of pDCs and pDC-related cells. To achieve our goal, we will take advantage of novel conditional knockout mouse models, transcription factor- overexpressing human cell lines, and high-dimensional approaches already established in our lab. We anticipate that findings from this proposal will bring into light novel mechanisms of transcriptional regulation that result in the positive outcome of innate immune responses against viruses. Importantly, our integrated approach will incorporate analyses of both mouse and human DCs; thus, it can reveal features that are conserved between species. This proposal has the potential to impact the rational design of therapeutic strategies by exploring regulatory programs determining the identity of key antiviral innate cells.

抽象的静脉细胞树突状细胞（PDC）和与PDC相关的细胞是发育相关的先天免疫细胞能够执行成功的抗病毒免疫反应所必需的多种功能，包括I型干扰素分泌和T细胞激活。 PDC和PDC相关的身份，即开发和功能细胞由转录因子（TFS）的精确相互作用控制。转录的严格调节程序对于促进对病原体的适当反应至关重要，同时避免对健康损害组织。因此，揭开PDC和PDC相关细胞的转录调控至关重要。使用高维度无偏的方法，我们最近发现了两个特定且高度高度的保守的TF 活跃在PDC和PDC相关细胞中，但没有其他DC子集。在两个具体目标中，我们建议探索这些TF在确定PDC和PDC相关细胞的开发和功能中的作用。实现我们的目标，我们将利用新型有条件敲除小鼠模型，转录因子 - 过表达的人类细胞系以及我们实验室已经建立的高维方法。我们期待该提案中的发现将导致转录调节的轻型新颖机制，从而导致对病毒的先天免疫反应的积极结果。重要的是，我们的综合方法将结合了小鼠和人类DC的分析；因此，它可以揭示在之间保守的功能物种。该建议有可能通过探索治疗策略的理性设计确定关键抗病毒先天细胞身份的调节计划。